Facilitation of Infantile Spasms by Partial Seizures

Summary: We report 16 patients with infantile spasms in whom onset of the clusters of spasms appeared to be triggered by close temporal association with partial seizures. Common features included the presence of focal cerebral lesions in 12 infants (3 were classifiable as cryptogenic); all had partial seizures with EEG localization, clusters of bilateral spasms always preceded by partial seizures, and response to adrenocorticotropic hormone (ACTH) and traditional antiepileptic drugs (AEDs) generally was poor. Three had complete agenesis of the corpus callosum, which argues against interhemispheric callosal spread of focal discharges resulting in the generalized spasms. Surgical cortical resections were performed in 6 of the infants, with good outcomes. This group of patients supports a model in which the spasms, although probably generated at a subcortical level, are facilitated or possibly induced by focal discharges from cortical pathology.     

Reduced ACTH Content in Cerebrospinal Fluid of Children Affected by Cryptogenic Infantile Spasms with Hypsarrhythmia

In view of the therapeutic efficacy of adrenocorticotropic hormone (ACTH) in the treatment of infantile spasms (IS) with hypsarrhythmia, we studied the cerebrospinal fluid (CSF) levels of ACTH in 15 children (4-10 months) affected by IS with hypsarrhythmia (eight cryptogenic forms, seven secondary to perinatal distress) and in age-matched controls. Lumbar puncture was performed in all but one case before any kind of treatment. In another case, CSF was collected 3 weeks after a spontaneous remission. Both ACTH and beta-endorphin (beta-EP), the other peptide related to the same precursor (proopiomelanocortin), were measured by specific radioimmunoassay after gel chromatography. While beta-EP levels were unchanged in the two groups of patients, ACTH concentrations of cryptogenic (3.75 +/- 2.40 fmol/ml, Mean +/- SD p less than 0.05) and secondary (6.36 +/- 3.70, NS) forms were lower than in controls (10.90 +/- 5.79). On the other hand, ACTH was higher in the case studied after therapy (9.0) and in the case presenting a spontaneous clinical and EEG remission (15.0). These data indicate that in children affected by IS with hypsarrhythmia (mainly of cryptogenic type), CSF levels of ACTH are lower, while levels of beta-EP remain normal. It would therefore appear that central ACTH content may play a possible role in the pathogenesis of IS with hypsarrhythmia.     

Evidence of Late-Onset Infantile Spasms

Summary: Purpose: To underline the unusual but possible Occurrence of epileptic spasms (ES) in children >1 year of age.
Methods: Cases in whom onset of spasms occurred after 1 year of age were identified through a retrospective review of the records of all patients referred for ES to the Saint-Vincent de Paul Hôpital (Paris) and American Memorial Hospital (Reims) between 1974 and 1994.
Results: Eighteen cases were identified among the 734 children referred for ES, 18 cases were identified where spasm onset time ranged from 12 to 38 months of age. In 1/3 of the cases, the diagnosis was suspected from the onset of clinical manifestations; in the remaining 2/3, diagnosis was delayed by a mean 6 months (range, 2–25 months). Neurobehavioral regression affected two-thirds of the patients. Modified hypsarrhythmia was present in 11 patients; all but one exhibited major and diffuse spike- and slow-wave activity. EEG abnormalities were detected in the frontal areas in 11 patients. Spasms were cryptogenic in 9 patients. Steroids were administered to 13 patients; these controlled the spasms in 6 patients. Outcome was favorable for both seizures; cognition favorable in only 2 of the 18 patients.
Conclusions: Beginning after the first year of life, ES, or late-onset infantile spasms, are distinct from early Lennox-Gastaut syndrome, although etiology, prognosis and treatment are similar to that for the classical infantile spasms.     

Localization of Focal Cortical Lesions Influences Age of Onset of Infantile Spasms

Summary: Purpose: To determine whether the localization of focal cerebral lesions affects age of onset of infantile spasms (IS).
Methods: We reviewed 216 cases of IS and identified patients with focal cerebral lesions confined to frontal, centrotemporoparietal, or occipital regions. The age of onset of spasms in each of the three groups was analyzed.
Results: Ninety-three patients were found to have focal cerebral lesions confined to one of the three regions previously described. The mean age of onset of IS was 3·36 ± 1·71 months in patients with occipital lesions, 6·26 ± 2·68 months in centrotemporoparietal lesions, and 9·83 ± 2·56 in frontal lesions.
Conclusions: Occipital lesions are found to be associated with earliest onset of spasms, whereas frontal lesions are rare and associated with latest spasms onset. The age distribution pattern of spasms onset according to localization of cortical lesion is in close correlation with that of normal sequence of brain maturation. This supports the hypothesis that cerebral lesions located in critical areas of brain maturation have a role in the genesis of infantile spasms.     

Seizures with Fever After Unprovoked Seizures: An Analysis in Children Followed from the Time of a First Febrile Seizure

Summary: Purpose: To determine how the onset of unprovoked seizures influences recurrence of seizures with fever in children followed from the time of a first febrile seizure.
Methods: In a prospective cohort of children (n = 428) identified at the time of a first febrile seizure, predictors of a second seizure with fever were identified. The occurrence of a first unprovoked seizure was treated as a time-dependent covariate in a Cox regression model rather than as a censoring point as it traditionally has been in the past.
Results: One hundred forty-three (33.4%) children had further seizures. Seven had further seizures with fever only after onset of unprovoked seizures. After adjustment was made for the four previously described predictors of recurrent febrile seizures (age at onset, family history, height of fever, and duration of fever), the onset of unprovoked seizures was associated with a rate ratio of 3.47 (p = 0.0015), indicating a large increase in the risk of further seizures with fever after onset of unprovoked seizures.
Conclusions: Young children who develop unprovoked seizures after a febrile seizure are at substantial risk for further seizures with fever. This may represent part of the spectrum of benign febrile seizures or it may represent the so-called "epilepsy triggered by fever" spectrum. It affects only a small proportion of children with febrile seizures; however, in some children, it may be useful information to consider when making treatment decisions.     

Diagnosis of Infantile Spasms, Lennox-Gastaut Syndrome, and Progressive Myoclonic Epilepsy

Summary:  The epilepsies of childhood are distinguished by an interesting dichotomy between the benign and catastrophic disorders. Approximately 50% of children outgrow childhood epilepsy as they mature; although the disorder is disruptive for children and families alike, it is not considered a medical disaster. The catastrophic epilepsies of childhood, in contrast, are associated with significant morbidity and mortality. Infantile spasms, Lennox-Gastaut syndrome, and the progressive myoclonic epilepsies are correlated with significant disability and a multiplicity of underlying etiologies. Accurate diagnosis of both the syndrome and the etiology is very important for treatment purposes, as well as for family education, since many of the disorders have a significant genetic component.     

Epidemiology of Infantile Spasms in Sweden

Summary: We performed a retrospective study of infantile spasms (IS) in 57 children (19 girls and 38 boys) from the east-central region of Sweden for the period 1987 1991. The incidence was 0.45/1,000newbornsa year, with a spread of 0.17–0.76 between the seven counties included. Forty-three cases (75%) were symptomatic and 14 (25%) were idiopathic. Cerebral malformations were diagnosed in 8 children, and chromosomal aberrations were diagnosed in 5. In addition, 2 children each were diagnosed as having tuberous sclerosis and neurofibromatosis. At follow-up, 57% in the idiopathic group had normal development, whereas 91% in the symptomatic group had died or developed a multihandicap. The value of modern neuroradiological techniques for etiological diagnosis is stressed.     

The Descriptive Epidemiology of Infantile Spasms Among Atlanta Children

PURPOSE: To determine the population-based epidemiology of infantile spasms (IS) among Atlanta children. METHODS: By using data from a cross-sectional, population-based surveillance system that included 21 EEG laboratories, we identified children born in 1975-1977 in metropolitan Atlanta with IS. Cumulative incidence up to age 2 years was estimated from the number of children with IS born in the study area in 1975-1977, and age-specific prevalence was calculated from the number of children previously diagnosed with IS who lived in the study area at age 10 years. Data regarding coexisting disabilities were available from the surveillance system for developmental disabilities. RESULTS: The cumulative incidence of IS was 2.9/10,000 live births; half of the children with IS had cryptogenic IS. The age-specific prevalence of IS was 2.0/10,000 among 10-year-old children. Eighty-three percent of 10-year-old children with a history of IS had mental retardation (MR, IQ < or =70); 56% of children with a history of IS had profound MR (IQ <20). Developmental outcome did not differ between the children with cryptogenic IS and those with symptomatic IS. Among the 10-year-old children with profound MR who were living in Atlanta at age 10 years, 12% had a history of IS. Fifty percent of children with IS developed Lennox-Gastaut syndrome (LGS) before age 11 years. CONCLUSIONS: The syndrome of IS is rare in the general population, yet a significant percentage of all children with profound MR and severe childhood epilepsy syndromes in the general population have a history of IS.     

Long-Term Prognosis of Patients with Infantile Spasms Following ACTH Therapy

The influence of ACTH on the prognosis of patients with infantile spasms remains controversial. We have examined retrospectively the long-term benefits of initially successful ACTH therapy in patients treated at this institution between 1961 and 1974. Individuals with equivocal or minimal improvement during ACTH therapy were excluded from this study. Eighteen affected infants showed a favorable early response consisting of cessation of seizures for at least 3 weeks during ACTH therapy and concurrent disappearance of the hypsarhythmic EEG pattern. Modal age at last follow-up was 5 years (range, 15 months to 16 years). Infantile spasms recurred in 7 patients (39%), and 8 patients subsequently had other seizure types. All epileptiform (spike) activity disappeared from the EEGs of 8 patients during ACTH therapy, but in 4 of these cases epileptiform activity was present in later tracings. In the remaining 10 patients the hypsarhythmic pattern disappeared in association with ACTH therapy, but the EEG remained epileptiform (often only in sleep). Later EEGs were free of epileptiform activity in 5 of the 10 patients whose tracings contained spike discharges in the early follow-up period. Four patients (22%) were seizure free and without intellectual impairment when last evaluated.     

Brief Atonia Associated with Electroencephalographic Paroxysm in an Infant with Infantile Spasms

The loss of muscular tone or muscular inhibition associated with sharp waves observed during abnormal tonic posture in a patient with infantile spasms of early onset is described. The latency between the beginning of a sharp wave and the muscular inhibition varied from 30 to 700 msec, and the duration of the inhibition ranged from 100 to 400 msec. These brief muscular inhibitions may sometimes precede tonic seizures, and these phenomena might be noticeable only in the state of steady tonic muscular contraction.     

Therapy of Infantile Spasms with Valproate: Results of a Prospective Study

In a prospective study, 22 children with recently manifested infantile spasms (18 patients with symptomatic and 4 with idiopathic infantile spasms) were treated with sodium valproate (VPA). Before VPA was instituted, a loading test was performed to exclude abnormal patterns of VPA metabolites by gas chromatography and mass spectroscopy of serum and urine. This test was repeated during VPA therapy; an abnormal pattern of VPA metabolites was not observed. VPA was started in increasing dosage until infantile spasms were controlled or a maximum dose of 100 mg/kg/day was reached. If VPA did not control seizures or at least reduce frequency significantly after a trial of 4-6 weeks, dexamathasone was added to VPA. If focal seizures occurred in association with localized epileptogenic EEG discharges, carbamazepine (CBZ) was added to VPA. After 4 weeks of VPA monotherapy, infantile spasms were controlled in 11 children. After 3 months of therapy, 16 children were free of seizures (14 patients VPA monotherapy), and 4 children had reduction of seizure frequency to less than 25%. VPA doses varied between 40 and 100 mg/kg/day (mean 74). The mean plasma concentration was 113 micrograms/ml (range 46-177). After 6 months of therapy, total seizure control was achieved in 20 of 22 patients (16 children VPA monotherapy). The mean observation time was 16 1/2 months (range 6-36 months). There were seven relapses in six children during the first 7 months of therapy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Reappraisal of Interictal Electroencephalograms in Infantile Spasms

Summary: To delineate interictal electroencephalographic (EEC) features before treatment of patients with clinically defined infantile spasms, EEGs of 82 infants having tonic spasms in clusters were analyzed by type of paroxysmal abnormalities, continuity, interhemispheric synchrony, topography, and wave component of hypsarrhythmia during wakefulness and sleep. Hypsarrhythmia occurred less frequently in wakefulness than in non-rapid eye movement (NREM) sleep at any age, least frequently in wakefulness after 1 year of age, and disappeared in rapid eye movement (REM) sleep at any age. The continuity of hypsarrhythmia changed with states, but did not change with age, and was greatest in wakefulness and stage 1 and decreased in stage 2–3. Interhemispheric synchrony increased with increasing age but decreased with advancing sleep stage. The term modified hypsarrhythmia should be discarded, and unusual features, if present, should be specified.     

Treatment of Infantile Spasms: Results of a Population-Based Study with Vigabatrin as the First Drug for Spasms

PURPOSE: The efficacy of a protocol consisting of vigabatrin (VGB) as the first and adrenocorticotropic hormone (ACTH) or valproate (VPA) as the second drug was studied in the treatment of newly diagnosed infantile spasms (IS) during 1994 to 1997 in a population-based design. METHODS: Only total disappearance of the spasms with a minimal duration of 1 month was accepted as a response. The treatment response was confirmed by video-EEG study. All infants were studied by magnetic resonance imaging (MRI) or computed tomography (CT) for etiology. RESULTS: Altogether 42 infants, 10 with cryptogenic and 32 with symptomatic etiology, were treated. Eleven (26%) responded to VGB, five (50%) with cryptogenic, and six (19%) with symptomatic etiology; 91% of infants responded to a dose of 50-100 mg/kg/day, and 82% of them within 1 week. ACTH was offered in combination with VGB to 22 and VPA to four infants for whom VGB failed. Eleven responded to ACTH and one to VPA. In total, 26 (62%) infants responded to the treatment protocol; all (100%) with cryptogenic etiology and 16 (50%) with symptomatic etiology. ACTH treatment was associated with more severe side effects than VGB or VPA. Only one infant relapsed after a spasm-free period with VGB of >4 months, but none after ACTH was combined with VGB. CONCLUSIONS: We suggest VGB as a first drug to all infants with IS. After a treatment trial of 10-14 days with increasing dose from 50 to 150 mg/kg, ACTH should be considered.     

Infantile Spasms in One Member of a Family with Benign Familial Neonatal Convulsions

Summary: Seven members of two generations experienced benign familial neonatal convulsions (BFNC) in the neonatal period and/or early infancy. All but 1 family member had a good prognosis. One family member with infantile spasms (IS) was delivered by cesarean section at 37 weeks gestation. Birth weight (2,562 g) was slightly lower than that of other family members. At age 20 days, adversive seizures started. At age 1 month, 10 days, she developed complex partial seizures (CPS) and IS. Interictal EEG showed hypsarrhythmia. Biochemical investigations and head magnetic resonance imaging (MRI) scan showed no abnormalities. Treatment with valproate (VPA) and carbamazepine (CBZ) stopped the seizures, and she had no seizures after age 3 months. Psychomotor development was moderately delayed at 8 months. This is the first reported case of a severe epilepsy, IS, in association with BFNC.     

Valproate Metabolites in Serum and Urine During Antiepileptic Therapy in Children with Infantile Spasms: Abnormal Metabolite Pattern Associated with Reversible Hepatotoxicity

The purpose of this study was to identify abnormal metabolite patterns of valproate (VPA) as possible early indicators of VPA-induced liver toxicity. In a prospective study, we determined serum and urine levels of VPA metabolites by gas chromatography-mass spectrometry (GC-MS) during the course of therapy in 25 children treated for infantile spasms with high VPA doses (less than or equal to 100 mg/kg body weight/day). Most patients had similar metabolite profiles: The main metabolites in serum were the beta-oxidation products (2-en-VPA and 3-keto-VPA) and the major diunsaturated metabolite 2,3'-dien-VPA. Glucuronide conjugates and the oxidation products represent the most abundant metabolites in urine. Other metabolites, including the potential hepatotoxin 4-en-VPA, were detected only in low concentrations. Two children had transiently aberrant metabolite profiles, indicating altered beta-oxidation, (levels of 2-en-VPA, 2,3'-dien-VPA, and 3-en-VPA were markedly increased) in connection with hepatomegaly and increased liver enzyme activities at a time when both had febrile infections and were receiving dexamethasone comedication. At no time were increased levels of 4-en-VPA or its derivatives detected. Establishing the VPA metabolite profile may aid in evaluation of patients who show signs and symptoms of liver dysfunction during VPA therapy. The present study shows that initial stages of hepatotoxicity reactions to VPA may be accompanied by characteristic changes in VPA metabolism; early detection of such abnormal metabolite patterns might decrease the risk of severe hepatic injury.     

A Pilot Study of Topiramate in the Treatment of Infantile Spasms

Summary: Purpose : West syndrome is a rare epileptic syndrome associated with infantile spasms, a specific abnormal electroencephalographic pattern (termed hypsarrhythmia). and mental retardation. Management of this disorder is difficult because current treatment regimens, including many anticonvulsants and hormones, are often ineffective. Topiramate (TPM) is a new antiepileptic drug that may be effective in pediatric epilepsies. We conducted a pilot study to test the effects of rapid TPM dosing in patients with refractory infantile spasms.
Methods: Eleven children with refractory infantile spasms were given an initial dose of 25 mg TPM per day in addition to their current therapy. Dosage was increased by 25 mg every 2–3 days until spasms were controlled, the maximal tolerated dose was reached, or the maximal dose of 24 mg/kg/day was achieved. Efficacy was primarily assessed by video EEG and secondarily by parental count of spasm frequency.
Results: Five (45%) subjects became spasm free during the study, with absence of infantile spasms and hypsarrhythmia (either classic or modified) proven by video EEG. Nine subjects, including the five spasm free, achieved a spasm reduction of 250%. Spasm frequency decreased from 25.6 f 19.3 to 6.9 r 5.9 spasmdday. Sixty-four percent of the subjects were able to achieve TPM monotherapy.
Conclusions: Results in this cohort of 11 patients with refractory disease show TPM to be a promising new agent for the treatment of infantile spasms.